Urology Practice Management August 2014 by Value-Based Cancer Care

FOR UROLOGISTS, PRACTICE MANAGERS, FINANCIAL COUNSELORS, AND REIMBURSEMENT SPECIALISTS™

AUGUST 2014

www.UroPracticeManagement.com

VOLUME 3 • NUMBER 4

Do’s and Don’ts in Efficient Use of Physician Physician-Hospital Assistants, Nurse Practitioners By Rosemary Frei, MSc Alignment, Part 2 rology practices in hospital and Courtney Ander By Max Reiboldt, CPA, President/ CEO, Coker Group, Alpharetta, GA

community settings can increase patient volume and rev enue with the efficient use of nurse practitioners (NPs) and physician assistants (PAs), according to a presen tation at the 2014 American Urological Association Practice Management Conference.

son, MPA, PA-C, Clinical Coordinator and Assis tant Pro fessor, Eastern Virginia Courtney Anderson, MPA, PA-C Medical School, Nor folk, VA, stated that the optimal use of these advanced practice clinicians Continued on page 8

Tips to Improve Upfront Collections in Urology Practices By Ellen Martin

s today’s healthcare climate evolves, physicians and hospi tals continue to explore options for alignment between private practices and healthcare systems. Interest in alignment perseveres despite a chal lenging healthcare environment, and economic, leadership, and structural Continued on page 4

ey elements in maintaining high efficiency in the revenue cycle and collection processes include a good dashboard reporting system, teamwork, and strong leadership, according to a presentation by Coker Group senior staff at the 2014 American Urological Association Practice Man agement Conference.

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FOR UROLOGISTS, PRACTICE MANAGERS, FINANCIAL COUNSELORS, AND REIMBURSEMENT SPECIALISTS™

Call for Papers

Do you have a practice management story to share

In your background as a urology practice manager, it’s likely there’s one business experience—and maybe more—that practice managers across the nation would want to read about.

High-interest topics include: the solution you found to a practice management challenge, reimbursement, your experience with EMR, Medicare audits, a memorable encounter that shaped the way you now run your business and/or practice medicine, or how you successfully integrated ancillary products and services into your practice as a revenue generator.

Send us your ideas!

Submit a 600- to 1500-word original article to Urology Practice Management, that your fellow practice managers will want to read.

Submit to: info@the-lynx-group.com UPM_73114

In This Issue

PUBLISHING STAFF Senior Vice President/Group Publisher Nicholas Englezos nenglezos@the-lynx-group.com Vice President, Director of Sales & Marketing Joe Chanley jchanley@the-lynx-group.com Publisher Cristopher Pires cpires@the-lynx-group.com Editorial Directors Dalia Buffery dbuffery@the-lynx-group.com Anne M. Cooper acooper@the-lynx-group.com

Associate Editor Lara J. Lorton Editorial Assistants Jennifer Brandt Cara Guglielmon Production Manager Marie RS Borrelli The Lynx Group President/CEO Brian Tyburski Chief Operating Officer Pam Rattananont Ferris Vice President of Finance Andrea Kelly Human Resources Jennine Leale Associate Director, Content Strategy & Development John Welz Director, Quality Control Barbara Marino Quality Control Assistant Theresa Salerno Director, Production & Manufacturing Alaina Pede Director, Creative & Design Robyn Jacobs Creative & Design Assistant Lora LaRocca Director, Digital Media Anthony Romano Web Content Managers David Maldonado Anthony Trevean Digital Programmer Michael Amundsen Meeting & Events Planner Linda Sangenito Senior Project Manager Jini Gopalaswamy Project Coordinator Deanna Martinez IT Specialist Carlton Hurdle Executive Administrator Rachael Baranoski Administrative Coordinator Stephanie Ramadan Office Coordinator Robert Sorensen Engage Healthcare Communications 1249 South River Road - Ste 202A Cranbury, NJ 08512 phone: 732-992-1880 fax: 732-992-1881

FEATURES Do’s and Don’ts in Physician-Hospital Alignment, Part 2.................................1 By Max Reiboldt, CPA

Efficient Use of Physician Assistants, Nurse Practitioners...................................1 By Rosemary Frei, MSc

Tips to Improve Upfront Collections in Urology Practices...................................1 By Ellen Martin

Delaying ADT for PSA-Only Relapse May Be a Viable Option for Men with Prostate Cancer and PSA-Only Relapses.................................10 By Wayne Kuznar

Aveed (Testosterone Undecanoate): A Novel Dosing Schedule Approved for Testosterone Replacement in Men with Hypogonadism.............................................................................................11 By Lisa A. Raedler, PhD, RPh

EDITORIAL ADVISORY BOARD Neil Baum, MD Practicing Urologist New Orleans, LA Cheris Craig, MBA, CMPE Chief Administrative Officer Urology of Greater Atlanta, LLC Atlanta, GA Michael deWitt Clayton, MD, FACS Urology Associates of San Luis Obispo, CA Rick Janss, MBA, CMPE Practice Administrator Clinical Urology Associates Gadsden, AL

John McMann, MS Administrator Advanced Urology Specialists, LLC Oxford, FL

James A. Sylora, MD Urologist AUS–Midwest Urology Evergreen Park, IL

Jonathan Oppenheimer, MD, FCAP Medical Director, Chief Pathologist Oppenheimer Urologic Reference Laboratory Nashville, TN

Sean M. Weiss, CCP-P, CCA-P, ACS-EM, CPC, CPC-P Vice President & Chief Compliance Officer DecisionHealth/ Professional Services Gaithersburg, MD

Jonathan Rubenstein, MD Director of Coding and Compliance Chesapeake Urology Baltimore, MD

MISSION STATEMENT Urology healthcare requires providers to focus attention on financial concerns and strategic decisions that affect the bottom line. To continue to provide the high-quality care urology patients deserve, providers must master the ever-changing business of urology. Urology Practice Management offers process solutions for members of the urology care team—medical, surgical, and radiation urologists, as well as executives, administrators, and coders/billers—to assist them in reimbursement, staffing, electronic health records, REMS, and compliance with state and federal regulations.

Urology Practice Management™, ISSN (requested), is published 6 times a year by Engage Healthcare Communications, LLC, 1249 South River Road, Cranbury, NJ 08512. Copyright © 2014 by Engage Healthcare Communications, LLC. All rights reserved. Urology Practice Management™ is a trademark of Engage Healthcare Communications, LLC. No part of this publication may be reproduced or transmitted in any form or by any means now or hereafter known, electronic or mechanical, including photocopy, recording, or any informational storage and retrieval sys tem, without written permission from the publisher. Printed in the United States of America. The ideas and opinions expressed in Urology Practice Management™ do not necessarily reflect those of the editorial board, the editors, or the publisher. Publication of an advertisement or other product mentioned in Urology Practice Management™ should not be construed as an endorsement of the product or the manufacturer’s claims. Readers are encouraged to contact the manufacturers about any features or limitations of products mentioned. Neither the editors nor the publisher assume any responsibility for any injury and/or damage to persons or property arising out of or related to any use of the material mentioned in this publication. POSTMASTER: Correspondence regarding subscriptions or change of address should be directed to CIRCULATION DIRECTOR, Urology Practice Management™, 1249 South River Road, Cranbury, NJ 08512. Fax: 732-992-1881. Yearly subscription rates: 1 year: $99.00 USD; 2 years: $149.00 USD; 3 years: $199.00 USD.

August 2014

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Physician–Hospital Alignment Series

Do’s and Don’ts in Physician–Hospital…Continued from the cover issues should all be explored with due diligence prior to agreeing on a final arrangement. In this article, the issues of governance and com pensation plans are explored as key elements for hospitals and physi cians to consider as they work toward developing successful align ment plans.

Governance One of the major hurdles to overcome within any alignment structure is the definition and understanding of governance and leadership responsibilities. This can be divided into several components. A major part of this discussion relates to operational decision-mak ing. Often, when they align with hospitals, physicians are challenged to give up day-to-day decision-mak ing responsibilities. In this instance, we are not considering clinical deci sion-making (discussed below), but the decisions that relate to the dayto-day management and operation of their businesses. In fact, in many instances physicians still do a better job of this than hospitals do, a prem ise that many hospitals are starting to concede. Thus, they are allowing physicians to have a great deal more input than they have had in the past. The structure of the alignment model will affect the ability for oper ational decision-making. A profes sional service agreement (PSA) model, for example, allows physi cians to have much decision-making ability on day-to-day operations. The issues surrounding day-to-day decision-making often involve staff supervision, which physicians usual ly can handle best. Ultimately, how ever, the hospital, as the employer, must have control and overall responsibility. Clinical decision-making is also an important part of the gover nance and leadership structure and

UROLOGY PRACTICE MANAGEMENT

definition. While physicians cer tainly are allowed to practice medi cine as they choose (even under full employment models), certain clini cal decision protocols must be con sidered. For example, when a prac

One of the major hurdles to overcome within any alignment structure is the definition and understanding of governance and leadership responsibilities.

tice becomes a part of a large hospital network, the implicit understanding and expectation is that they will primarily consider referring to other physicians within that aligned network, although they are not legally and contractually bound to do this. Other clinical decision-making should continue to rest with the physicians, though the utilization of ancillary services and rehabilitation should be directed toward the aligned hospital net work. There is absolutely no re quirement under any aligned model for hospitals to direct physicians on how best to practice medicine. While there is much more deci sion-making allowance within the typical governance and leadership structures, ultimately the hospital (under a fully aligned model) should have certain reserve powers. These are usually “big picture” rights, entailing major decisions or expen ditures. They could, however, be

August 2014

drilled down into detailed deci sions, such as the hospital’s ultimate approval for any staff and for adding providers. The purpose of the reserve pow ers is to provide the hospital with the ultimate check and balance, knowing that under a fully aligned model it is in control of most major decisions. Under a PSA model where the practice does retain its responsibility for managing the practice, ultimately certain deci sions that rest with that manage ment structure would still be those of the practice and not subject to the reserve powers. Also, organizational chart proto cols are a consideration of leader ship and governance, as in the structure of the entity and how the management processes are carried out. Certain practices, for example, could be structured as a group prac tice subsidiary, or, if not officially and legally, this would be organized (at least in substance) as a stand alone subset of the overall hospital’s employed physician network entity. Some hospitals will establish an institute model wherein the aligned practice(s) are separated into a major service line structure. Within that institute, there are individual governance, organizational, and operational understandings and protocols—again, within the defini tion of being a part of the overall hospital/health system organization. Many decisions must be consid ered within the leadership and gov ernance structure as the alignment process unfolds. We recommend that a checklist of all the key deriv atives be considered.

Compensation Plan Physician compensation is a major part of any transaction con cerning physicians and hospitals. This does not have to be under an

Physician–Hospital Alignment Series

employment setting, although it is often the case. If not employment, one of the fuller forms of alignment (such as a PSA) is often applicable. As such, there are several model alternatives. These vary from heavi ly productivity-based incentive plan models to nonproductivity-based incentives. Often and particularly as accountable care and changing reim bursement paradigms start to apply in many instances, the compensa tion model is truly a hybrid (ie, a combination of several of these incentives, both productivity, and nonproductivity-based). From the productivity side, the most prominent form of incentive is through a relative value unit (RVU) format. Often, RVUs are used because they are relatively easy to understand and they tend to be payer blind. Thus, physicians can work diligently within a practice and not worry about the actual reimbursement that is involved, as RVUs do not differentiate from one payer to another. Typically, their compensation plan involves being paid a certain amount per work RVU (wRVU), and as the RVUs accumulate, the total dollars of compensation do, as well. Other productivity-based models can be tied to encounters, charges, and actual payments. There is no partic ular right or wrong way; it requires a concerted effort of analysis and deliberation (even some negotia tions) to determine the most acceptable structure. Nonproductivity-based incen tives are typically tied to patient satisfaction, quality outcomes, costsavings, and overall conduct. These incentives can be structured in a variety of ways and can be set up so that (1) productivity thresholds must be met, and (2) a portion of what would otherwise be paid from the productivity measurement would have to be earned through meeting certain nonproductivi

ty-based performance thresholds. Thus, the models can have a wide range of variations, and, as long as genuine incentives to perform and meet the expectations of the crite ria are present, the chances are good that the compensation model will be successful.

profit margins are less after the transaction. There are ways to miti gate this issue through calibrating an appropriate rate per wRVU that is still within legally permissible/fair market value parameters, but possi bly better than the practice realizes in actuality prior to the alignment transaction. Quality and shared savings incentives are increasingly popular as accountable care forms of reim bursement (ie, reimbursement that is not based strictly on productivity and a fee-for-service payment) gain ground. Realizing that it is import ant to measure overall performance based on the quality of the out comes and the cost to incur the services, more compensation plans are mirroring these forms of reim bursement, which is certain to continue to be the case in the future. Finally, here is a word of caution relative to the overall compliance standards that must be met whenever physicians are compensated by a hospital. The term fair market value is a readily used concept, which entails the determination that the rate of compensation is consistent with market standards and norms. This is often reviewed and opined upon by an expert inde pendent party that is not directly involved in establishing the rates or the overall compensation plan. In addition, compensation must meet existing commercially reasonable standards within the particular area and specialty involved. Also, there are many compensation structures where multiple portals of pay are provided to the physicians. For example, perhaps the physician is employed and generates a compen sation structure from that employ ment contract. In addition, he is subject to a medical directorship and is compensated. Perhaps the physician is also compensated for

Max Reiboldt, CPA

Physician compensation is a major part of any transaction concerning physicians and hospitals. This does not have to be under an employment setting, although it is often the case. Many employed physicians ex pect a base or guaranteed rate of pay. This is negotiable but is often the case, at least for a limited period of time. Ancillary services are also key to the compensation structure, if those services remain within the practice after alignment. If they do, the phy sician may be able to share in a portion of the profits from those ancillary services (just as they do today in private practice). If not, the ancillary services cannot be paid to the physicians and may be a reason why overall productivity and

August 2014

Continued on page 7

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AUA Practice Management Conference

Tips to Improve Upfront Collections…Continued from the cover Vice President, Coker Group, Alpharetta, GA. “They need to be able to diagram those functions out, be able to elucidate those functions to staff so that everyone understands very completely what’s going on.”

ment. We just upgraded to this new computer system, and for whatever reason it won’t allow me to make an appointment for anyone with a bal ance over 60 days. Having said that, I am going to put you on the list.

“The office manager, administrator, or person who oversees the revenue cycle needs a real solid understanding of how the process works from upfront check-in, checkout, collection of copays, deductibles…all the way through to the end of the process.” —Jeffrey Gorke, MBA It is also important to have clear strategies in place, with involve ment and education of staff and providers, such as a collection and billing timeline that is developed with staff input, a financial policy that is delineated in a patient wel come package, and regular billing audits, Mr Gorke said. It can be very helpful to create tools to manage patient collections, he noted. Even though patients may have a contractual obligation to pay, he said, the job of the front office staff members who collect the money is extremely difficult. Jeffery Daigrepont, EFPM, who is also a Senior Vice President at Coker Group, suggested creative ways to collect money. “For example, [the person at the front desk could say,] ‘Mrs Jones, I’m happy to schedule your appoint

UROLOGY PRACTICE MANAGEMENT

Come in at 3:30, and I am going to have Jeff from the back office come up here and spend a few minutes with you,’” Mr Daigrepont said. “That is not threatening, it is not adversarial. In fact, it sounds like the front desk person is helping Mrs Jones out.” Strategies for management in clude analyzing and then updating fee schedules, and locating con tracts with payers and understand ing the terms, said Mr Gorke. “Most contracts with payers are evergreen, so they are just going to roll over. The unfortunate problem is, if you have them tied into Medicare, and Medicare drops your rates, then your commercial payer is going to drop their rates too,” Mr Gorke said. “This is all part and parcel of the process of managing and under standing the dollars that are coming

August 2014

in the door. If Blue Cross Blue Shield, for instance, is tied to Medicare, and Medicare drops 10% next year, then Blue Cross Blue Shield is going to drop, roughly speaking, 10%.” Developing relationships with a key contact at each of the major payers is also important, he said. Managers should work with these contacts to “understand payer tactics and common denial reasons that those payers will deploy.” Fur thermore, involving and educating providers and managing their expec tations is “the lifeblood of the prac tice,” said Mr Gorke. “Unless you are running a 20% overhead rate and the money is good and everyone is happy, I would suggest to you it is probably key to show the physicians how the dollars are flowing in and flowing out relative to the revenue cycle collections process….These are the guys and gals who go out and actually generate the money, so they need to be involved in this process,” suggested Mr Gorke. Mr Daigrepont said that there must also be considerable focus on front office functions. This can be aided by diagramming some of the workflows and analyzing the most common reasons for unpaid accounts. “In study after study we have done, 90% of the reasons why doc tors do not get paid is attributable to your front desk,” said Mr Daigrepont. “That is where a dash board [comes in]. It is very inexpen sive and allows for early interven tion because you guys, as leaders, can see right there on your desktop where you are at any given moment of your accounts receivable cycle…. Trust me, you will find payers are shorting you a few dollars here and there, but over time that adds up to a lot of money.” It is also a very good practice to set benchmarks in the gross collec

AUA Practice Management Conference

tion rate, net collection rate, days in accounts receivable, and adjust ment percentage (total adjustments divided by the total fee-for-service charges), advised Mr Daigrepont. “Knowing where your benchmarks are is very important, in terms of maximizing your profitability.” Some practice managers may want to consider outsourcing the billing, or even all of the business end of the practice. “A lot of us in leadership are somewhat overwhelmed with all of the things we have to worry about, so it is appealing sometimes to just get rid of all our IT infrastructure, our services, and just go with a straight service fee [billing compa ny],” Mr Daigrepont said. “Having said that, they can be very expen

sive, especially in urology. What I would strongly encourage you to do is tie their compensation to bench

collections, cash-paying patients, to be a lesser percentage.” Mr Daigrepont urged participants

“Knowing where your benchmarks are is very important, in terms of maximizing your profitability.” —Jeffery Daigrepont, EFPM

marks, so if they want that 5%, 6% of collections as their fee, they have to hit certain target levels. Also, I would tier your over-the-counter

to use caution when considering outsourced billing, saying, “No one is going to care as much about your money as you do.” l

Do’s and Don’ts in Physician–Hospital…Continued from page 5 call responsibilities. All of these things must be considered within the compliance standard so this stacking concept does not ultimate ly result in a total pay package that is beyond the realm of reason (ie, that exceeds the test for fair market value/commercially reasonable rates). Thus, when the compensa tion plan is structured, it should be considered in totality, not just as stand-alone components. Thus, there are numerous mod els to consider—no matter the alignment model. Even within a PSA structure (also referred to as “employment lite”), the payments can be varied and tied to certain levels of incentives. There are other forms of compensation, such as payment for malpractice premi ums or tail premiums, sign-on and/ or retention bonuses, and other forms of pay—all of which must be

considered in the broad context of physician compensation. For mod

the pay structure is frequently set with fewer incentives (though some incentives could be in place within these structures). Often, a guaranteed rate per hour is applied, but that payment must be consis tent with the total amount of time worked and the value for that work per hour. Usually, this varies great ly from one specialty to another. l

Many decisions must be considered within the leadership and governance structure as the alignment process unfolds. We recommend that a checklist of all the key derivatives be considered.

This article is the second in a 3-part series addressing physician–hospital alignments. Part 1 focused on pretransactional due diligence and structural design processes as they pertain to these alignments. Part 2 is focused on governance and compensation plans. Watch for the final installment of this series—highlighting ongoing relationships and unwind possibilities—in the October issue.

els that do not entail employment or other forms of full alignment,

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AUA Practice Management Conference

Efficient Use of Physician…Continued from the cover (APCs) hinges on allowing them to use the full scope of their training and ability. Citing data from a 2013 issue of Urology Times, Ms Anderson noted that there are approximately 3000 urology APCs in the United States and growing.1

and then, if so, determine which services they will delegate to the APCs. Instead of plucking from the relatively small pool of current urology APCs, she said, practices can hire NPs or PAs who have been in similar specialties and are

“If you don’t have the infrastructure in place to deal with multiple different providers, people in different settings at the same time, if you don’t have enough nursing staff or medical assistants, enough people with knowledge of proper scheduling…it won’t fly. Make sure your group is stable, then know how to bill for it. It is so important.” — Courtney Anderson, MPA, PA-C

“Most practices tend to underuti lize physician assistants and nurse practitioners,” said Ms Anderson. “They put them in where they are just gathering the [patient] history and not allowing them to provide diagnosis and management. They are putting them in the office and having them sit on the phone with pharmacies or insurance companies trying to deal with those adminis trative tasks.… If it is more the administrative aspect that your practices need, hire someone less expensive who can sit on the phone and do that.” When considering whether to hire an APC, it is important to perform a gap analysis or a needs assessment, determine whether the physicians are willing to use APCs,

proficient in performing procedures that are similar to urology proce dures, or hire newly graduated APCs who they can train gradually under close supervision. One of the most common ways to deploy APCs is patient history-taking, physical examination, initial diagnosis, and new and returning patient manage ment. This frees physicians to focus on complex procedures, finalize dis cussions regarding surgery, and manage treatment of patients with complicated conditions, explained Ms Anderson. In a team model, APCs can work with different supervising physi cians on different days, work with physicians off the same schedule, or, if they have more experience, they can run their own clinics on days

UROLOGY PRACTICE MANAGEMENT

August 2014

when the physician is in the operat ing room. Care by APCs can be billed under their own provider numbers, with the reimbursement rate for Medicare patients being 85% of the physician’s Medicare fee schedule. When appropriate, their services can be billed at 100% of the physician’s rate under Medicare’s “incident to” category, if certain criteria are met. “As long as the physician goes in and sees those patients and has some input, all are considered 100% physician care in the sched ule, because [it’s “incident to” care, and] you’re going to put it under the physician’s provider identifica tion number.” Another approach to using APCs is the access to care or gatekeeper model, in which the APCs have a narrower scope of practice: initiat ing workups on new patients, screening for surgical conditions, transferring care of surgery candi dates to the most appropriate urolo gists, and providing emergency de partment follow-ups. A third model is the specialist model, which is used by several large academic genitourinary practices, and which also focuses on APC pro vision of nonsurgical care. APCs would see patients independently and, therefore, use their own provid er numbers for billing. The length of patient visits with fully trained APCs is approximately equal to the length of patient visits with physicians, except for the more subspecialized patients, Ms Anderson said. Billing for hospital-employed APCs’ services is somewhat simi lar, except that there is no “inci dent to” category. Instead, billing under a physician’s provider num ber is done under shared visit crite ria, which follow the “3-sames and a some” rule, explained Ms Anderson. This means the APC

AUA Practice Management Conference

and the physician have to have the same employer, have to see the same patient on the same day, and there has to be some face-to-face time between the patient and the physician. Shared visit billing per tains only to evaluation and man agement and cannot be done for an initial consult or procedures. A relatively new phenomenon involves APCs performing ultra sound-guided prostate biopsies and flexible cystoscopy, noted Ms Anderson. She cited that at Emory University, hundreds of prostate bi opsies are conducted annually, and the university’s 4 PAs perform about 70% to 80% of them. The PAs’ reim bursement rate is about 90% of the urologists’ rate, and they are paid about a third of what the physician would be paid. The same may occur with cystoscopies, with more APCs perhaps doing these for difficult cath eter placement, said Ms Anderson. She also described 4 factors that are necessary for the successful inte gration of APCs, particularly in hospital-based practices but also in freestanding clinics2: (1) whether the group’s physicians buy into the APC paradigm, including agreeing to provide the necessary training on an ongoing basis; (2) whether the group is stable enough to support the incorporation of APCs; (3) whether there is an accurate under standing of how to bill for APC services; and (4) whether qualified

APC candidates are available. “If you don’t have the infrastruc ture in place to deal with multiple different providers, people in differ ent settings at the same time, if you don’t have enough nursing staff or

sicians, said Ms Anderson. “On any individual day, don’t have 4 physicians expecting to be able to utilize that nurse practi tioner or PA at their whim…,” Ms Anderson said. It also may be opti mal to have APCs perform activi ties such as surgical assisting and patient rounds on days separate from clinic-based activities to avoid shifting patients between cli nicians if responsibilities at the hospital take longer than expected. Ms Anderson explained that although scheduling could be chal lenging at first, particularly in some of the larger hospitals where it is uncertain at any one time how many consults or patients you’re going to have, it will become easier with practice. It can take effort to determine what roles APCs can play in each urology practice, and to find the right people to fill those roles, but it can be well worth it, Ms Anderson concluded. l

It can take effort to determine what roles APCs can play in each urology practice, and to find the right people to fill those roles, but it can be well worth it, Ms Anderson concluded. medical assistants, enough people with knowledge of proper schedul ing…it won’t fly. Make sure your group is stable, then know how to bill for it. It is so important.” Hospital-based APCs can perform patient rounds, consults/histories, physicals, admissions, and discharg es; act as initial responders; perform appropriate diagnostic and therapeu tic procedures; be the genitourinary representatives in multidisciplinary care teams; and be surgical first assis tants.2 It is best for APCs to perform these activities alongside 1 or 2 phy

References

1. Hilton L. Non-physician providers: allied or dis parate? Urology Times. July 30, 2013. http://urol ogytimes.modernmedicine.com/urology-times/news/ non-physician-providers-allied-or-disparate. Accessed July 9, 2014. 2. Use of Non-physician Clinical Staff in Hospitalist Programs – Chapter 8. Society of Hospital Medicine. www.google.com/url?sa=t&rct=j&q=&esrc=s& source=web&cd=1&cad=rja&uact=8&ved=0C CkQFjAA&url=http%3A%2F%2Fwww.hospital medicine.org%2FCMDownload.aspx%3FContent Key%3Ded0642ef-e72e-428e-bb5b-5bec8dee83d0% 26ContentItemKey%3D85c8f112-e195-4e8b-b0c0-f8 9f2705edf1&ei=co3GU6PbLY3gsATx94CwAQ&us g=AFQjCNFdaTJf_lZgPcXvFIUaA90Kimt6k g&sig2=uQU2NGcVvQM_aI8uAMCxow. Accessed July 16, 2014.

Urology Practice Management is now available online at: www.UroPracticeManagement.com

August 2014

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ASCO 2014 Highlights

Delaying ADT for PSA-Only Relapse May Be a Viable Option for Men with Prostate Cancer and PSA-Only Relapses By Wayne Kuznar

Chicago, IL—Delaying androgen deprivation therapy (ADT) for at least 2 years did not lead to worse overall survival or prostate cancer– specific survival compared with the initiation of ADT within 3 months of rising prostate-specific antigen (PSA) in men with PSA-only relapse (ie, biochemical relapse) after the primary treatment of

rush to treatment, and the results provide reassurance for us about withholding ADT.” Lead investigator Xabier Garciade-Albeniz, MD, ScM, Research As sociate, Harvard University School of Public Health, Boston, said, “Imme diate versus deferred ADT for men with a PSA-only recurrence is a grey area.” He noted that the National

“These findings suggest that there may be no need to rush to ADT. Obviously, this is an observational study with several limitations. A large ongoing randomized phase 3 trial is looking at this question and results of that trial will answer the question and serve as the gold standard.” —Xabier Garcia-de-Albeniz, MD, ScM

prostate cancer with surgery or radiation, according to the results of a large population-based study presented at the 2014 American Society of Clinical Oncology (ASCO) meeting and highlighted at a press briefing. Commenting on the study, ASCO President Clifford A. Hudis, MD, Chief, Breast Cancer Medi cine Service, Memorial Sloan Ket tering Cancer Center, New York, said, “This study may provide reas surance about deferring ADT for quality-of-life reasons. We can tell patients that they don’t have to

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Comprehensive Cancer Network guidelines say that the role of ADT in this setting is a “therapeutic dilem ma,” noting that “These findings sug gest that there may be no need to rush to ADT. Obviously, this is an observational study with several lim itations. A large ongoing randomized phase 3 trial is looking at this ques tion and results of that trial will answer the question and serve as the gold standard.” The study was based on data for more than 14,000 patients partici pating in the prospective Cancer of the Prostate Strategic Urologic

August 2014

Research Endeavor (CaPSURE) registry based at the University of California, San Francisco. Overall, 2022 men had a PSA-only relapse (defined as >.02 ng/mL or 3 rising PSA levels, asymptomatic, or no metastasis) after curative surgery or radiation. Patients with a PSA-only relapse received immediate ADT (ie, within 3 months of rising PSA) or deferred ADT (ie, at least 2 years after PSA relapse, or for metastasis, symptoms, or short PSA doubling time). The median time from primary treatment to PSA relapse was 27 months. The median follow-up after PSA relapse was 41 months. The median age of the patients was 69 years (range, 63-74 years), 33.8% of the patients had a Gleason score of >7, and 31.8% received radiation as primary treatment. During follow-up, 176 deaths were reported; 37 of these deaths were from prostate cancer. The 5-year survival rates were 85.1% for the deferred ADT group and 87.2% for immediate ADT. The 10-year survival rate was iden tical in both groups, at 71.6%. Person-months were used as the unit for analysis (instead of persons); 84,716 person-months were assigned to deferred ADT, and 13,889 per son-months were assigned for the immediate ADT strategy. Dr Garcia-de-Albeniz and other experts said that these results could be included in discussions with patients who had a PSA-only relapse who may want to delay ADT because of unwanted side effects or other reasons. l

Drug Update

Aveed (Testosterone Undecanoate): A Novel Dosing Schedule Approved for Testosterone Replacement in Men with Hypogonadism By Lisa A. Raedler, PhD, RPh, Medical Writer

n men, hypogonadism (or tes tosterone deficiency) occurs when the testes fail to produce physiological levels of testosterone and the normal number of sper matozoa.1 This condition is caused by disruption at 1 or more levels of the hypothalamic-pituitary-go nadal axis.1 Primary hypogonadism can result from testicular injury, autoimmune disorders, and genetic disorders (ie, Klinefelter syndrome), infection, liver disease, kidney disease, radiation, or surgery.2,3 In contrast, a faulty hypothalamus or pituitary gland causes central hypo gonadism.2 Certain medications (ie, steroids, long-term opiate use), genetic disorders, bleeding disorders, nutritional deficiencies, radiation, surgery, and pituitary tumors can result in central hypogonadism.2 Affecting approximately 39% of men aged ≥45 years in the United States, hypogonadism is diagnosed more often as men grow older.3,4 The signs and symptoms of hypo gonadism include decreased body hair, enlarged breasts, muscle weak ness, sexual dysfunction, fatigue, and depression.3 The loss of libido, impotence, infertility, and osteopo rosis are also characteristic of this condition.3 According to the Endocrine Society, the diagnosis of hypogo nadism should be made in men who have consistent signs and symptoms, as well as low total tes tosterone levels.1 A serum total testosterone level of 300 ng/dL is Copyright © 2014 American Health & Drug Benefits. All rights reserved.

considered the lower limit of nor mal.1 Identification of the condi tion is important, in part because hypogonadism is often associated with 1 of several diseases and med ical conditions, including obesity, diabetes, hypertension, hyperlip idemia, osteoporosis, and asthma or chronic obstructive pulmonary disease.2,4

transfer testosterone to women or to children.7 Hypogonadism and its related comorbidities result in a significant cost burden for the US healthcare system.8 Retrospective analysis of an administrative claims database of 55 large, self-insured US compa nies has documented that compared with controls, male employees with hypogonadism were signifi cantly more likely to have comor bidities, including hyperlipidemia, hypertension, back or neck pain, mental disorders, and HIV/AIDS.8 Men with hypogonadism also had significantly higher rates of hospi talization, emergency department visits, outpatient physician visits, and prescription medication use.8 In that analysis, the direct and indi rect healthcare costs were higher for men with hypogonadism compared with the controls. These costs were primarily related to the manage ment of comorbid conditions asso ciated with hypogonadism.8

Hypogonadism and its related comorbidities result in a significant cost burden for the US healthcare system. Pharmacologic treatments for hypogonadism are designed to replace deficient testosterone and to improve symptoma tology. Testosterone re placement therapy has been shown to restore sexual function and mus cle strength, prevent osteoporosis, increase energy, and enhance sex drive.5,6 Testosterone replacement products are available in multiple for mulations, such as a skin patch, topi cal gel, depot injection, buccal tablet, and subcutaneous pellet implant.1,2 Despite the variety of route of admin istration options, however, today’s testosterone replacement therapies have many shortcomings; some require twice-daily application, some men cannot tolerate the buccal tablet on their gums, transdermal patch es can cause local skin irritation, and gel formulations can potentially

August 2014

New Treatment Option for Hypogonadism: Testosterone Undecanoate On March 6, 2014, the US Food and Drug Administration (FDA) approved testosterone un decanoate (Aveed; Endo Pharmaceuticals) for testosterone replacment therapy in adult males for conditions associat ed with a deficiency or absence of endogenous testosterone, including primary hypogonadism (con genital or acquired) and hypogonadotrop ic hypo gonadism (congenital or acquired).9 Continued on page 12

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Drug Update

Aveed (Testosterone Undecanoate)…Continued from page 11 Testosterone undecanoate is a long-acting depot formulation of testosterone formulated in refined castor oil and benzyl benzoate.10 The new drug has a novel dosing sched ule: a single intramuscular (IM) injection is given initially, followed by a second injection 4 weeks later. Subsequent injections are given every 10 weeks thereafter.10 The FDA approved testosterone undecanoate after reviewing data from an 84-week phase 3 clinical trial of men with hypogonadism in the United States.7 This trial showed that testosterone undeca noate increased and maintained mean serum testosterone levels within the adult male reference range at all of the time points that were measured.7 The FDA approval of testoster one undecanoate includes a boxed warning regarding anaphylaxis and serious pulmonary oil microemul sion (POME) reactions.10 The FDA approval also requires the manufac turer to provide a Risk Evaluation and Mit igation Strategy (REMS) program that includes pre scriber education and certification, as well as restricted product distribution.9 Testosterone undecanoate is a Schedule III controlled substance in the Controlled Substances Act.10

Dosing and Administration A dose of 3 mL (750 mg) of tes tosterone undecanoate is injected intramuscularly at initiation, then at 4 weeks, and at every 10 weeks thereafter. Dosage titration is not

Clinical Trials In the single-arm, open-label, 84-week multicenter phase 3 clin ical trial of testosterone un deca noate, 130 men with hypogonadism received 3-mL (750-mg) IM injec tions at weeks 0 and 4, and every 10 weeks thereafter.7,10 A total of 9 injections were administered over 84 weeks.7 The primary efficacy end point of the trial was the percentage of men with average serum total testos terone concentration (Cavg) within the normal range (300-1000 ng/ dL) after the third injection, or steady state.10 The secondary end point was the percentage of men with maximum total testosterone concentration (Cmax) above 3 pre determined limits: >1500 ng/dL, between 1800 and 2499 ng/dL, and >2500 ng/dL.10 The average serum prostate-spe cific antigen (PSA) increased from 1.0 ± 0.8 ng/mL at study baseline to 1.5 ± 1.3 ng/mL at the conclusion of the 84-week phase 3 study.10 During the 84-week treatment peri od, 10.9% of patients whose base line PSA was <4 ng/mL had a post baseline serum PSA of >4 ng/mL.10 In total, 725 men with hypo gonadism received IM testoster

Mechanism of Action Testosterone undecanoate injec tion is an ester of testosterone.10 Testosterone and other endogenous androgens are responsible for the growth and development of male sex organs and the maintenance of secondary sex characteristics.10

necessary.10 The drug is injected into the gluteus medius muscle, which is located in the upper outer quadrant of the buttock. To minimize the risk of intravascular injection, testoster one undecanoate should be injected deeply into the gluteal muscle based on the recommended procedures for IM drug administration.10 After each injection, patients should be observed for 30 min utes in a certified healthcare setting to monitor for, and to potentially treat, serious POME or anaphylaxis reactions.10

UROLOGY PRACTICE MANAGEMENT

August 2014

one undecanoate in 7 controlled clinical trials.10 The doses of IM testosterone undec anoate varied from 750 mg to 1000 mg, and the dose frequency ranged from every 9 weeks to every 14 weeks.10 In sever al of these trials, the loading doses of testosterone undec anoate were administered at therapy initiation. The 84-Week Phase 3 Trial In the 84-week trial, eligible patients included men with primary or secondary hypogonadism who were aged ≥18 years.10 All had a morning screening testosterone con centration of <300 ng/dL.10 Patients with an American Urological Association International Prostate Symptom Score of ≥15, or those with significant prostatic symp toms, were ineligible for this study.7 Patients with serious psychiatric disease or uncontrolled medical ill ness, and those who used any sex hormones or steroidal anabolic drug supplements within 28 days before enrollment screening or at any time during the course of the study were not included in the study.7 Among the 130 study partic ipants, mean screen ing testoster one concentration was 215 ng/dL and mean body mass index was 32 kg/m2.10 Their mean age was 54 years.10 The majority (75%) of patients were white and were diag nosed with primary hypogonadism (approximately 70%).7,10 Of the 130 patients, 38% were naïve to testos terone replacement therapy.7 The phase 3 study demonstrat ed that testosterone undecanoate injection was efficacious in treating hypogonadism in adult men.10 Of the 130 patients, 117 completed 24 weeks of the study and were includ ed in the pharmacokinetics evalua tion. The majority (94%) of patients maintained a Cavg within the nor mal range (300-1000 ng/dL).10 Of

Drug Update

the 117 patients who completed 24 weeks, 6 (5.1%) had a Cavg below the normal range (<300 ng/dL) and 1 (0.9%) patient was above the nor mal range (>1000 ng/dL).10 The percentage of patients with a Cmax of >1500 ng/dL was 7.7%. None of the patients had a Cmax of >1800 ng/dL.10 The mean serum total testos terone pharmacokinetic parameters at steady state for the 117 patients who completed 24 weeks of the study are summarized in Table 1. Adverse Events In the 84-week study of tes tosterone undecanoate, the most frequently reported adverse events were acne, injection site pain, an increase in serum PSA to >4 ng/ mL, hypogonadism, and increased estradiol (Table 2).10 A total of 7 (4.6%) patients who participated in the 84-week clini cal trial of testosterone undecanoate discontinued the trial because of adverse reactions, which included increased hematocrit, increased estra diol, increased PSA, prostate can cer, mood swings, prostatic dysplasia, acne, and deep vein thrombosis.10 Adverse events that were report ed by ≥3% of patients in the 7 clinical trials, irrespective of the investigator’s assessment of their relationship to the study medica tion, included sinusitis, prostatitis, arthralgia, nasopharyngitis, upper respiratory tract infection, bronchi tis, back pain, hypertension, diar rhea, and headache.10 In controlled clinical trials of IM testosterone undec a noate, adverse events attributable to POME and anaphylaxis were reported. In the 84-week clinical trial of testosterone undecanoate, 1 patient experienced a mild cough ing fit that lasted 10 minutes after his third injection. This event was retrospectively attributed to POME.

In another clinical trial of IM testosterone undeca noate dosed at 1000 mg, a male patient experienced the urge to cough and respiratory distress at 1 minute after his tenth injection, which was also retrospectively attribut ed to POME.10 A total of 9 POME events in 8 patients and 2 anaphy laxis events among 3556 patients treated with IM testosterone undecanoate in 18 clinical trials were judged to have occurred during a review that involved adju dication of all cases meeting specific criteria.10

Mean Serum Total Testosterone Table 1 Concentrations at Steady State for Testosterone Undecanoate 750 mg Concentration level

Mean (SD) serum total testosterone concentration, ng/dL (N = 117)

Cavg (0-10 wks)

495 (142)

Cmax

891 (345)

Cmin

324 (99)

Cavg indicates average concentration; Cmax, maximum concentration; Cmin, minimum concentration; SD, standard deviation. Source: Aveed (testosterone undecanoate) injection prescribing information; March 2014.

occur during or immediately after the IM injection of testosterone un decanoate 1000 mg (4 mL).10 Most of these events were of a few minutes in duration and resolved with supportive measures. In other cases, symptoms lasted up to several hours and emergency care and/or hospitalization was required.10 Episodes of anaphylaxis, includ ing life-threatening reactions, have also been reported after IM injec tion of testosterone undecanoate.10 Anaphylaxis and/or serious POME reactions can occur after any injection of testosterone undec anoate, including after the initial dose. Patients with suspected hyper sensitivity reactions to testosterone undecanoate should not be treated again with it.10 After each injection of testoster one undecanoate, patients should be observed in the healthcare setting for 30 minutes to provide appro priate medical treatment should any serious POME and anaphylaxis events occur.10 REMS program. Because of the risk for serious POME and anaphy laxis, testosterone un decanoate is distributed through a restricted pro gram, the Aveed REMS Program. Healthcare providers who prescribe

Contraindications Men with breast cancer or with known or suspected prostate cancer should not use testosterone undecanoate.10 Women who are or may become pregnant or who are breastfeeding should not take testosterone undec anoate. Testosterone can cause fetal harm when administered to a pregnant woman and may also cause serious adverse reactions in nursing infants.10 Androgen expo sure to a fetus or a nursing infant may result in varying degrees of virilization.10 Men with known hypersensitiv ity to testosterone undecanoate or any of its ingredients (ie, testoster one undecanoate, refined castor oil, or benzyl benzoate) should not use testosterone undecanoate.10 Warnings and Precautions Boxed warning regarding serious POME reactions, anaphylaxis. Testosterone undecanoate carries a boxed warning regarding ana phylaxis and serious POME re ac tions, such as cough, urge to cough, dyspnea, hyper hidrosis, throat tightening, chest pain, dizziness, and syncope.10 POME reactions can

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Continued on page 14

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Drug Update

Aveed (Testosterone Undecanoate)…Continued from page 13 Table 2

The 84-Week Clinical Study of Testosterone Undecanoate: Adverse Events Reported in ≥1% of Patients Patients using testosterone undecanoate 750 mg, N (%) (N = 153)

Adverse eventsa Acne

8 (5.2)

Injection site pain

7 (4.6)

PSA increased

7 (4.6)

Estradiol increased

4 (2.6)

Hypogonadism

4 (2.6)

Fatigue

3 (2)

Irritability

3 (2)

Hemoglobin increased

3 (2)

Insomnia

3 (2)

Mood swings

3 (2)

Aggression

2 (1.3)

Ejaculation disorder

2 (1.3)

Injection site erythema

2 (1.3)

Hematocrit increased

2 (1.3)

Hyperhidrosis

2 (1.3)

Prostate cancer

2 (1.3)

Prostate induration

2 (1.3)

Weight increased

2 (1.3)

NOTE: A total of 7 (4.6%) patients discontinued the trial because of adverse reactions. a Defined as a serum PSA concentration >4 ng/mL. PSA indicates prostate-specific antigen. Source: Aveed (testosterone undecanoate) injection prescribing information; March 2014.

testosterone undecanoate must be certified with the REMS program before ordering or dispensing testos terone undecanoate.10 Healthcare settings must be certified with the REMS program and must have cer tified healthcare providers before ordering and dispensing testoster one undecanoate. Healthcare set tings must also have onsite access to equipment and trained personnel to manage serious POME and anaphy laxis.10 (Additional information is available at www.AveedREMS.com

UROLOGY PRACTICE MANAGEMENT

and via 855-755-0494.10) Worsening of benign prostatic hyperplasia/risk for prostate cancer. Patients with benign prostatic hyperplasia (BPH) who use andro gens, including testosterone undec anoate, are at an increased risk for, and should be monitored for, wors ening of the signs and symptoms of BPH. Patients receiving andro gens, including testosterone undec anoate, also have an increased risk for prostate cancer and should be evaluated before starting and during

August 2014

testosterone undecanoate therapy.10 Polycythemia. Increases in hematocrit may require the discontin uation of testosterone undecanoate, because increases in red blood cell mass can affect thromboembolic event risk.10 Hematocrit should be checked before starting testosterone undecanoate treatment, every 3 to 6 months while receiving treatment, and then annually. If hematocrit becomes elevated, therapy should be stopped until it decreases to an acceptable level.10 Use in women. Testosterone undecanoate is not indicated for use in women because of a lack of controlled evaluations in women and potential virilizing effects.10 Effects on spermatogenesis. Spermatogenesis may be suppressed with large doses of exogenous androgens, including testosterone undecanoate. This can adversely affect sperm count.10 Hepatic events. The contin ued use of high doses of orally active 17-alpha-alkyl androgens (eg, methyltestosterone) has been associated with serious hepatic adverse events, including peliosis hepatis (which can be fatal), hepat ic neoplasms, cholestatic hepatitis, and jaundice. Long-term therapy with IM testosterone enanthate, which elevates blood testoster one levels for long time periods, has led to multiple hepatic ade nomas. Although testosterone undecanoate is not known to pro duce these effects, patients should be advised to report any signs or symptoms of hepatic dys function (eg, jaundice). If these occur, the cause should be evaluated and testosterone undeca noate should be discontinued.10 Edema. Androgens, includ ing testosterone undecanoate, can increase sodium and water reten tion. In patients with preexisting

Drug Update

cardiac, renal, or hepatic disease, edema can be a serious compli cation. Diuretic therapy may be required and testosterone undeca noate should be discontinued.10 Gynecomastia. Gynecomastia may occur and persist in men receiving testosterone replacement therapy for hypogonadism.10 Sleep apnea. Hypogonadal men receiving testosterone replacement therapy may develop sleep apnea, particularly obese men and those with chronic lung disease.10 Lipids. Dose adjustment of lipid- lowering drugs or discontinuation of testosterone therapy may be required if changes in serum lipid profile are observed.10 Hypercalcemia. Patients with cancer who are at risk of hypercal cemia and associated hypercalciuria should only use androgens, includ ing testosterone undecanoate, with caution. Serum calcium concentra tions should be regularly monitored in these patients.10 Decreased thyroxine-binding globulin. Thyroxine-binding globu lin concentrations may be lower in patients using androgens, including testosterone undecanoate. Because free thyroid hormone concentra tions remain unchanged, thyroid

dysfunction has not been observed.10

convenient treatment option. Participating in the REMS pro gram associated with this therapy is important to ensure that it is only used in men for whom the benefits outweigh the risks. l

Specific Populations The safety and effectiveness of testosterone undecanoate have not been established in males aged <18 years. The use of testosterone undecanoate in these patients may result in acceleration of bone age and premature closure of epiphyses.10 Whether the efficacy or safe ty of testosterone un d ecanoate in men aged >65 years differs from younger patients cannot be determined, because the number of geriatric patients participat ing in controlled clinical studies was insufficient. Data in geriatric patients are insufficient to assess the risks for cardiovascular disease or prostate cancer.10

References

1. Bhasin S, Cunningham GR, Hayes FJ, et al; for the Task Force, Endocrine Society. Testosterone therapy in men with androgen deficiency syndromes: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2010;95:2536-2559. 2. MedlinePlus. Hypogonadism. Updated December 22, 2012. www.nlm.nih.gov/medlineplus/ency/article/ 001195.htm. Accessed March 14, 2014. 3. Dandona P, Rosenberg MT. A practical guide to male hypogonadism in the primary care setting. Int J Clin Pract. 2010;64:682-696. 4. Mulligan T, Frick MF, Zuraw QC, et al. Prevalence of hypogonadism in males aged at least 45 years: the HIM study. Int J Clin Pract. 2006;60:762-769. 5. Arver S, Dobs AS, Meikle AW, et al. Long-term efficacy and safety of a permeation-enhanced testos terone transdermal system in hypogonadal men. Clin Endocrinol. 1997;47:727-737. 6. McNicholas TA, Dean JD, Mulder H, et al. A novel testosterone gel formulation normalizes andro gen levels in hypogonadal men, with improvements in body composition and sexual function. BJU Int. 2003;91:69-74. 7. Wang C, Harnett M, Dobs AS, Swerdloff RS. Pharmacokinetics and safety of long-acting testosterone undecanoate injections in hypogonadal men: an 84-week phase III clinical trial. J Androl. 2010;31:457-465. 8. Kaltenboeck A, Foster S, Ivanova J, et al. The direct and indirect costs among U.S. privately insured employ ees with hypogonadism. J Sex Med. 2012;9:2438-2447. 9. US Center for Drug Evaluation and Research. Aveed approval letter. March 5, 2014. www. accessdata.fda.gov/drugsatfda_docs/appletter/2014/ 022219Orig1s000ltr.pdf. Accessed March 15, 2014. 10. Aveed (testosterone undecanoate) injection [prescribing information]. Malvern, PA: Endo Pharmaceuticals Solutions Inc; March 2014.

Conclusion The March 2014 FDA approv al of a new dosing schedule for testosterone undecanoate pro vides patients with hypogonadism a novel and convenient adminis tration alternative compared with the currently available testosterone replacement preparations. For men with this condition, testosterone undecanoate offers a long-acting formulation as an effective and

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August 2014

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ZYTIGA® (abiraterone acetate) Tablets Brief Summary of Prescribing Information. INDICATIONS AND USAGE ZYTIGA is a CYP17 inhibitor indicated in combination with prednisone for the treatment of patients with metastatic castration-resistant prostate cancer. CONTRAINDICATIONS Pregnancy: ZYTIGA can cause fetal harm when administered to a pregnant woman. ZYTIGA is not indicated for use in women. ZYTIGA is contraindicated in women who are or may become pregnant. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, apprise the patient of the potential hazard to the fetus and the potential risk for pregnancy loss [see Use in Specific Populations]. WARNINGS AND PRECAUTIONS Hypertension, Hypokalemia and Fluid Retention Due to Mineralocorticoid Excess: ZYTIGA may cause hypertension, hypokalemia, and fluid retention as a consequence of increased mineralocorticoid levels resulting from CYP17 inhibition [see Clinical Pharmacology (12.1) in full Prescribing Information]. In the two randomized clinical trials, grade 3 to 4 hypertension occurred in 2% of patients, grade 3 to 4 hypokalemia in 4% of patients, and grade 3 to 4 edema in 1% of patients treated with ZYTIGA [see Adverse Reactions]. Co-administration of a corticosteroid suppresses adrenocorticotropic hormone (ACTH) drive, resulting in a reduction in the incidence and severity of these adverse reactions. Use caution when treating patients whose underlying medical conditions might be compromised by increases in blood pressure, hypokalemia or fluid retention, e.g., those with heart failure, recent myocardial infarction or ventricular arrhythmia. Use ZYTIGA with caution in patients with a history of cardiovascular disease. The safety of ZYTIGA in patients with left ventricular ejection fraction <50% or New York Heart Association (NYHA) Class III or IV heart failure (in Study 1) or NYHA Class II to IV heart failure (in Study 2) was not established because these patients were excluded from these randomized clinical trials [see Clinical Studies (14) in full Prescribing Information]. Monitor patients for hypertension, hypokalemia, and fluid retention at least once a month. Control hypertension and correct hypokalemia before and during treatment with ZYTIGA. Adrenocortical Insufficiency: Adrenal insufficiency occurred in the two randomized clinical studies in 0.5% of patients taking ZYTIGA and in 0.2% of patients taking placebo. Adrenocortical insufficiency was reported in patients receiving ZYTIGA in combination with prednisone, following interruption of daily steroids and/or with concurrent infection or stress. Use caution and monitor for symptoms and signs of adrenocortical insufficiency, particularly if patients are withdrawn from prednisone, have prednisone dose reductions, or experience unusual stress. Symptoms and signs of adrenocortical insufficiency may be masked by adverse reactions associated with mineralocorticoid excess seen in patients treated with ZYTIGA. If clinically indicated, perform appropriate tests to confirm the diagnosis of adrenocortical insufficiency. Increased dosage of corticosteroids may be indicated before, during and after stressful situations [see Warnings and Precautions]. Hepatotoxicity: In the two randomized clinical trials, grade 3 or 4 ALT or AST increases (at least 5X ULN) were reported in 4% of patients who received ZYTIGA, typically during the first 3 months after starting treatment. Patients whose baseline ALT or AST were elevated were more likely to experience liver test elevation than those beginning with normal values. Treatment discontinuation due to liver enzyme increases occurred in 1% of patients taking ZYTIGA. No deaths clearly related to ZYTIGA were reported due to hepatotoxicity events. Measure serum transaminases (ALT and AST) and bilirubin levels prior to starting treatment with ZYTIGA, every two weeks for the first three months of treatment and monthly thereafter. In patients with baseline moderate hepatic impairment receiving a reduced ZYTIGA dose of 250 mg, measure ALT, AST, and bilirubin prior to the start of treatment, every week for the first month, every two weeks for the following two months of treatment and monthly thereafter. Promptly measure serum total bilirubin, AST, and ALT if clinical symptoms or signs suggestive of hepatotoxicity develop. Elevations of AST, ALT, or bilirubin from the patient’s baseline should prompt more frequent monitoring. If at any time AST or ALT rise above five times the ULN, or the bilirubin rises above three times the ULN, interrupt ZYTIGA treatment and closely monitor liver function. Re-treatment with ZYTIGA at a reduced dose level may take place only after return of liver function tests to the patient’s baseline or to AST and ALT less than or equal to 2.5X ULN and total bilirubin less than or equal to 1.5X ULN [see Dosage and Administration (2.2) in full Prescribing Information]. The safety of ZYTIGA re-treatment of patients who develop AST or ALT greater than or equal to 20X ULN and/or bilirubin greater than or equal to 10X ULN is unknown. Increased ZYTIGA Exposures with Food: ZYTIGA must be taken on an empty stomach. No food should be consumed for at least two hours before the dose of ZYTIGA is taken and for at least one hour after the dose of ZYTIGA is taken. Abiraterone Cmax and AUC0-∞ (exposure) were increased up to 17and 10-fold higher, respectively, when a single dose of abiraterone acetate was administered with a meal compared to a fasted state. The safety of these increased exposures when multiple doses of abiraterone acetate are taken with food has not been assessed [see Dosage and Administration (2.1) and Clinical Pharmacology (12.3) in full Prescribing Information].

ZYTIGA® (abiraterone acetate) Tablets ADVERSE REACTIONS The following are discussed in more detail in other sections of the labeling: • Hypertension, Hypokalemia, and Fluid Retention due to Mineralocorticoid Excess [see Warnings and Precautions]. • Adrenocortical Insufficiency [see Warnings and Precautions]. • Hepatotoxicity [see Warnings and Precautions]. • Increased ZYTIGA Exposures with Food [see Warnings and Precautions]. Clinical Trial Experience: Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. Two randomized placebo-controlled, multicenter clinical trials enrolled patients who had metastatic castration-resistant prostate cancer who were using a gonadotropin-releasing hormone (GnRH) agonist or were previously treated with orchiectomy. In both Study 1 and Study 2 ZYTIGA was administered at a dose of 1,000 mg daily in combination with prednisone 5 mg twice daily in the active treatment arms. Placebo plus prednisone 5 mg twice daily was given to control patients. The most common adverse drug reactions (≥10%) reported in the two randomized clinical trials that occurred more commonly (>2%) in the abiraterone acetate arm were fatigue, joint swelling or discomfort, edema, hot flush, diarrhea, vomiting, cough, hypertension, dyspnea, urinary tract infection and contusion. The most common laboratory abnormalities (>20%) reported in the two randomized clinical trials that occurred more commonly (≥2%) in the abiraterone acetate arm were anemia, elevated alkaline phosphatase, hypertriglyceridemia, lymphopenia, hypercholesterolemia, hyperglycemia, elevated AST, hypophosphatemia, elevated ALT and hypokalemia. Study 1: Metastatic CRPC Following Chemotherapy: Study 1 enrolled 1195 patients with metastatic CRPC who had received prior docetaxel chemotherapy. Patients were not eligible if AST and/or ALT ≥2.5X ULN in the absence of liver metastases. Patients with liver metastases were excluded if AST and/or ALT >5X ULN. Table 1 shows adverse reactions on the ZYTIGA arm in Study 1 that occurred with a ≥2% absolute increase in frequency compared to placebo or were events of special interest. The median duration of treatment with ZYTIGA was 8 months. Table 1: Adverse Reactions due to ZYTIGA in Study 1 ZYTIGA with Placebo with Prednisone (N=791) Prednisone (N=394) System/Organ Class All Grades1 Grade 3-4 All Grades Grade 3-4 Adverse reaction % % % % Musculoskeletal and connective tissue disorders Joint swelling/ 29.5 discomfort2 4.2 23.4 4.1 Muscle discomfort3 26.2 3.0 23.1 2.3 General disorders Edema4 26.7 1.9 18.3 0.8 Vascular disorders Hot flush 19.0 0.3 16.8 0.3 Hypertension 8.5 1.3 6.9 0.3 Gastrointestinal disorders Diarrhea 17.6 0.6 13.5 1.3 Dyspepsia 6.1 0 3.3 0 Infections and infestations Urinary tract infection 11.5 2.1 7.1 0.5 Upper respiratory tract infection 5.4 0 2.5 0 Respiratory, thoracic and mediastinal disorders Cough 10.6 0 7.6 0 Renal and urinary disorders Urinary frequency 7.2 0.3 5.1 0.3 Nocturia 6.2 0 4.1 0 Injury, poisoning and procedural complications Fractures5 5.9 1.4 2.3 0 Cardiac disorders 6 Arrhythmia 7.2 1.1 4.6 1.0 Chest pain or chest discomfort7 3.8 0.5 2.8 0 Cardiac failure8 2.3 1.9 1.0 0.3

ZYTIGA® (abiraterone acetate) Tablets

1 Adverse events graded according to CTCAE version 3.0 2 Includes terms Arthritis, Arthralgia, Joint swelling, and Joint stiffness 3 Includes terms Muscle spasms, Musculoskeletal pain, Myalgia,

Table 3: Adverse Reactions in ≥5% of Patients on the ZYTIGA Arm in Study 2 (continued) ZYTIGA with Placebo with Prednisone (N=542) Prednisone (N=540) 1 System/Organ Class All Grades Grade 3-4 All Grades Grade 3-4 Adverse reaction % % % % Renal and urinary disorders Hematuria 10.3 1.3 5.6 0.6 Skin and subcutaneous tissue disorders Rash 8.1 0.0 3.7 0.0 1 Adverse events graded according to CTCAE version 3.0 2 Includes terms Edema peripheral, Pitting edema, and Generalized edema 3 Includes terms Arthritis, Arthralgia, Joint swelling, and Joint stiffness Table 4 shows laboratory abnormalities that occurred in greater than 15% of patients, and more frequently (>5%) in the ZYTIGA arm compared to placebo in Study 2. Grade 3-4 lymphopenia (9%), hyperglycemia (7%) and high alanine aminotransferase (6%) occurred at a greater than 5% rate in the ZYTIGA arm.

Musculoskeletal discomfort, and Musculoskeletal stiffness terms Edema, Edema peripheral, Pitting edema, and Generalized edema 5 Includes all fractures with the exception of pathological fracture 6 Includes terms Arrhythmia, Tachycardia, Atrial ﬁbrillation, Supraventricular tachycardia, Atrial tachycardia, Ventricular tachycardia, Atrial ﬂutter, Bradycardia, Atrioventricular block complete, Conduction disorder, and Bradyarrhythmia 7 Includes terms Angina pectoris, Chest pain, and Angina unstable. Myocardial infarction or ischemia occurred more commonly in the placebo arm than in the ZYTIGA arm (1.3% vs. 1.1% respectively). 8 Includes terms Cardiac failure, Cardiac failure congestive, Left ventricular dysfunction, Cardiogenic shock, Cardiomegaly, Cardiomyopathy, and Ejection fraction decreased 4 Includes

Table 2 shows laboratory abnormalities of interest from Study 1. Grade 3-4 low serum phosphorus (7%) and low potassium (5%) occurred at a greater than or equal to 5% rate in the ZYTIGA arm. Table 2: Laboratory Abnormalities of Interest in Study 1 Abiraterone (N=791) Placebo (N=394) Laboratory All Grades Grade 3-4 All Grades Grade 3-4 Abnormality (%) (%) (%) (%) Hypertriglyceridemia 62.5 0.4 53.0 0 High AST 30.6 2.1 36.3 1.5 Hypokalemia 28.3 5.3 19.8 1.0 Hypophosphatemia 23.8 7.2 15.7 5.8 High ALT 11.1 1.4 10.4 0.8 High Total Bilirubin 6.6 0.1 4.6 0 Study 2: Metastatic CRPC Prior to Chemotherapy: Study 2 enrolled 1088 patients with metastatic CRPC who had not received prior cytotoxic chemotherapy. Patients were ineligible if AST and/or ALT ≥2.5X ULN and patients were excluded if they had liver metastases. Table 3 shows adverse reactions on the ZYTIGA arm in Study 2 that occurred with a ≥2% absolute increase in frequency compared to placebo. The median duration of treatment with ZYTIGA was 13.8 months. Table 3: Adverse Reactions in ≥5% of Patients on the ZYTIGA Arm in Study 2 ZYTIGA with Placebo with Prednisone (N=542) Prednisone (N=540) 1 System/Organ Class All Grades Grade 3-4 All Grades Grade 3-4 Adverse reaction % % % % General disorders Fatigue 39.1 2.2 34.3 1.7 Edema2 25.1 0.4 20.7 1.1 Pyrexia 8.7 0.6 5.9 0.2 Musculoskeletal and connective tissue disorders Joint swelling/ discomfort3 30.3 2.0 25.2 2.0 Groin pain 6.6 0.4 4.1 0.7 Gastrointestinal disorders Constipation 23.1 0.4 19.1 0.6 Diarrhea 21.6 0.9 17.8 0.9 Dyspepsia 11.1 0.0 5.0 0.2 Vascular disorders Hot ﬂush 22.3 0.2 18.1 0.0 Hypertension 21.6 3.9 13.1 3.0 Respiratory, thoracic and mediastinal disorders Cough 17.3 0.0 13.5 0.2 Dyspnea 11.8 2.4 9.6 0.9 Psychiatric disorders Insomnia 13.5 0.2 11.3 0.0 Injury, poisoning and procedural complications Contusion 13.3 0.0 9.1 0.0 Falls 5.9 0.0 3.3 0.0 Infections and infestations Upper respiratory tract infection 12.7 0.0 8.0 0.0 Nasopharyngitis 10.7 0.0 8.1 0.0

Table 4: Laboratory Abnormalities in >15% of Patients in the ZYTIGA Arm of Study 2 Abiraterone (N = 542) Placebo (N = 540) Laboratory Grade 1-4 Grade 3-4 Grade 1-4 Grade 3-4 Abnormality % % % % Hematology Lymphopenia 38.2 8.7 31.7 7.4 Chemistry Hyperglycemia1 56.6 6.5 50.9 5.2 High ALT 41.9 6.1 29.1 0.7 High AST 37.3 3.1 28.7 1.1 Hypernatremia 32.8 0.4 25.0 0.2 Hypokalemia 17.2 2.8 10.2 1.7 1Based on non-fasting blood draws Cardiovascular Adverse Reactions: In the combined data for studies 1 and 2, cardiac failure occurred more commonly in patients treated with ZYTIGA compared to patients on the placebo arm (2.1% versus 0.7%). Grade 3-4 cardiac failure occurred in 1.6% of patients taking ZYTIGA and led to 5 treatment discontinuations and 2 deaths. Grade 3-4 cardiac failure occurred in 0.2% of patients taking placebo. There were no treatment discontinuations and one death due to cardiac failure in the placebo group. In Study 1 and 2, the majority of arrhythmias were grade 1 or 2. There was one death associated with arrhythmia and one patient with sudden death in the ZYTIGA arms and no deaths in the placebo arms. There were 7 (0.5%) deaths due to cardiorespiratory arrest in the ZYTIGA arms and 3 (0.3%) deaths in the placebo arms. Myocardial ischemia or myocardial infarction led to death in 3 patients in the placebo arms and 2 deaths in the ZYTIGA arms. DRUG INTERACTIONS Drugs that Inhibit or Induce CYP3A4 Enzymes: Based on in vitro data, ZYTIGA is a substrate of CYP3A4. In a dedicated drug interaction trial, co-administration of rifampin, a strong CYP3A4 inducer, decreased exposure of abiraterone by 55%. Avoid concomitant strong CYP3A4 inducers during ZYTIGA treatment. If a strong CYP3A4 inducer must be co-administered, increase the ZYTIGA dosing frequency [see Dosage and Administration (2.3) and Clinical Pharmacology (12.3) in full Prescribing Information]. In a dedicated drug interaction trial, co-administration of ketoconazole, a strong inhibitor of CYP3A4, had no clinically meaningful effect on the pharmacokinetics of abiraterone [see Clinical Pharmacology (12.3) in full Prescribing Information]. Effects of Abiraterone on Drug Metabolizing Enzymes: ZYTIGA is an inhibitor of the hepatic drug-metabolizing enzyme CYP2D6. In a CYP2D6 drug-drug interaction trial, the Cmax and AUC of dextromethorphan (CYP2D6 substrate) were increased 2.8- and 2.9-fold, respectively, when dextromethorphan was given with abiraterone acetate 1,000 mg daily and prednisone 5 mg twice daily. Avoid co-administration of abiraterone acetate with substrates of CYP2D6 with a narrow therapeutic index (e.g., thioridazine). If alternative treatments cannot be used, exercise caution and consider a dose reduction of the concomitant CYP2D6 substrate drug [see Clinical Pharmacology (12.3) in full Prescribing Information].

ZYTIGA® (abiraterone acetate) Tablets

In vitro, ZYTIGA inhibits CYP2C8. There are no clinical data on the use of ZYTIGA with drugs that are substrates of CYP2C8. However, patients should be monitored closely for signs of toxicity related to the CYP2C8 substrate if used concomitantly with abiraterone acetate.

OVERDOSAGE Human experience of overdose with ZYTIGA is limited. There is no specific antidote. In the event of an overdose, stop ZYTIGA, undertake general supportive measures, including monitoring for arrhythmias and cardiac failure and assess liver function. Storage and Handling: Store at 20°C to 25°C (68°F to 77°F); excursions permitted in the range from 15°C to 30°C (59°F to 86°F) [see USP controlled room temperature]. Based on its mechanism of action, ZYTIGA may harm a developing fetus. Therefore, women who are pregnant or women who may be pregnant should not handle ZYTIGA without protection, e.g., gloves [see Use in Specific Populations].

USE IN SPECIFIC POPULATIONS Pregnancy: Pregnancy Category X [see Contraindications].: ZYTIGA can cause fetal harm when administered to a pregnant woman based on its mechanism of action and findings in animals. While there are no adequate and well-controlled studies with ZYTIGA in pregnant women and ZYTIGA is not indicated for use in women, it is important to know that maternal use of a CYP17 inhibitor could affect development of the fetus. Abiraterone acetate caused developmental toxicity in pregnant rats at exposures that were lower than in patients receiving the recommended dose. ZYTIGA is contraindicated in women who are or may become pregnant while receiving the drug. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, apprise the patient of the potential hazard to the fetus and the potential risk for pregnancy loss. Advise females of reproductive potential to avoid becoming pregnant during treatment with ZYTIGA. In an embryo-fetal developmental toxicity study in rats, abiraterone acetate caused developmental toxicity when administered at oral doses of 10, 30 or 100 mg/kg/day throughout the period of organogenesis (gestational days 6-17). Findings included embryo-fetal lethality (increased post implantation loss and resorptions and decreased number of live fetuses), fetal developmental delay (skeletal effects) and urogenital effects (bilateral ureter dilation) at doses ≥10 mg/kg/day, decreased fetal ano-genital distance at ≥30 mg/kg/day, and decreased fetal body weight at 100 mg/kg/day. Doses ≥10 mg/kg/day caused maternal toxicity. The doses tested in rats resulted in systemic exposures (AUC) approximately 0.03, 0.1 and 0.3 times, respectively, the AUC in patients. Nursing Mothers: ZYTIGA is not indicated for use in women. It is not known if abiraterone acetate is excreted in human milk. Because many drugs are excreted in human milk, and because of the potential for serious adverse reactions in nursing infants from ZYTIGA, a decision should be made to either discontinue nursing, or discontinue the drug taking into account the importance of the drug to the mother. Pediatric Use: Safety and effectiveness of ZYTIGA in pediatric patients have not been established. Geriatric Use: Of the total number of patients receiving ZYTIGA in phase 3 trials, 73% of patients were 65 years and over and 30% were 75 years and over. No overall differences in safety or effectiveness were observed between these elderly patients and younger patients. Other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. Patients with Hepatic Impairment: The pharmacokinetics of abiraterone were examined in subjects with baseline mild (n=8) or moderate (n=8) hepatic impairment (Child-Pugh Class A and B, respectively) and in 8 healthy control subjects with normal hepatic function. The systemic exposure (AUC) of abiraterone after a single oral 1,000 mg dose of ZYTIGA increased by approximately 1.1-fold and 3.6-fold in subjects with mild and moderate baseline hepatic impairment, respectively compared to subjects with normal hepatic function. No dosage adjustment is necessary for patients with baseline mild hepatic impairment. In patients with baseline moderate hepatic impairment (ChildPugh Class B), reduce the recommended dose of ZYTIGA to 250 mg once daily. If elevations in ALT or AST >5X ULN or total bilirubin >3X ULN occur in patients with baseline moderate hepatic impairment, discontinue ZYTIGA treatment [see Dosage and Administration (2.1) and Clinical Pharmacology (12.3) in full Prescribing Information]. The safety of ZYTIGA in patients with baseline severe hepatic impairment has not been studied. These patients should not receive ZYTIGA. For patients who develop hepatotoxicity during treatment, interruption of treatment and dosage adjustment may be required [see Dosage and Administration (2.2) in full Prescribing Information, Warnings and Precautions, and Clinical Pharmacology (12.3)] in full Prescribing Information. Patients with Renal Impairment: In a dedicated renal impairment trial, the mean PK parameters were comparable between healthy subjects with normal renal function (N=8) and those with end stage renal disease (ESRD) on hemodialysis (N=8) after a single oral 1,000 mg dose of ZYTIGA. No dosage adjustment is necessary for patients with renal impairment [see Dosage and Administration (2.1) and Clinical Pharmacology (12.3) in full Prescribing Information].

PATIENT COUNSELING INFORMATION See FDA-approved patient labeling (Patient Information) • Patients should be informed that ZYTIGA and prednisone are used together and that they should not interrupt or stop either of these medications without consulting their physician. • Patients receiving GnRH agonists should be informed that they need to maintain this treatment during the course of treatment with ZYTIGA and prednisone. • Patients should be informed that ZYTIGA must not be taken with food and that no food should be consumed for at least two hours before the dose of ZYTIGA is taken and for at least one hour after the dose of ZYTIGA is taken. They should be informed that the tablets should be swallowed whole with water without crushing or chewing. Patients should be informed that taking ZYTIGA with food causes increased exposure and this may result in adverse reactions. • Patients should be informed that ZYTIGA is taken once daily and prednisone is taken twice daily according to their physician’s instructions. • Patients should be informed that in the event of a missed daily dose of ZYTIGA or prednisone, they should take their normal dose the following day. If more than one daily dose is skipped, patients should be told to inform their physician. • Patients should be apprised of the common side effects associated with ZYTIGA, including peripheral edema, hypokalemia, hypertension, elevated liver function tests, and urinary tract infection. Direct the patient to a complete list of adverse drug reactions in PATIENT INFORMATION. • Patients should be advised that their liver function will be monitored using blood tests. • Patients should be informed that ZYTIGA may harm a developing fetus; thus, women who are pregnant or women who may be pregnant should not handle ZYTIGA without protection, e.g., gloves. Patients should also be informed that it is not known whether abiraterone or its metabolites are present in semen and they should use a condom if having sex with a pregnant woman. The patient should use a condom and another effective method of birth control if he is having sex with a woman of child-bearing potential. These measures are required during and for one week after treatment with ZYTIGA. Manufactured by: Patheon Inc. Mississauga, Canada Manufactured for: Janssen Biotech, Inc. Horsham, PA 19044 © Janssen Biotech, Inc. 2012 Revised: September 2013 003185-130920

INDICATION and IMPORTANT SAFETY INFORMATION about ZYTIGA® (abiraterone acetate) INDICATION ZYTIGA® (abiraterone acetate) in combination with prednisone is indicated for the treatment of patients with metastatic castration-resistant prostate cancer (mCRPC). IMPORTANT SAFETY INFORMATION

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Contraindications ZYTIGA® (abiraterone acetate) is not indicated for use in women. ZYTIGA® can cause fetal harm (Pregnancy Category X) when administered to a pregnant woman and is contraindicated in women who are or may become pregnant. Hypertension, Hypokalemia and Fluid Retention Due to Mineralocorticoid Excess Use with caution in patients with a history of cardiovascular disease or with medical conditions that might be compromised by increases in blood pressure, hypokalemia, or fluid retention. ZYTIGA® may cause hypertension, hypokalemia, and fluid retention as a consequence of increased mineralocorticoid levels resulting from CYP17 inhibition. Safety has not been established in patients with LVEF <50% or New York Heart Association (NYHA) Class III or IV heart failure (in Study 1) or NYHA Class II to IV heart failure (in Study 2) because these patients were excluded from these randomized clinical trials. Control hypertension and correct hypokalemia before and during treatment. Monitor blood pressure, serum potassium, and symptoms of fluid retention at least monthly. Adrenocortical Insufficiency (AI) AI was reported in patients receiving ZYTIGA® in combination with prednisone, after an interruption of daily steroids and/or with concurrent infection or stress. Use caution and monitor for symptoms and signs of AI if prednisone is stopped or withdrawn, if prednisone dose is reduced, or if the patient experiences unusual stress. Symptoms and signs of AI may be masked by adverse reactions associated with mineralocorticoid excess seen in patients treated with ZYTIGA®. Perform appropriate tests, if indicated, to confirm AI. Increased dosages of corticosteroids may be used before, during, and after stressful situations. Hepatotoxicity Monitor liver function and modify, withhold, or discontinue ZYTIGA® dosing as recommended (see Prescribing Information for more information). Measure serum transaminases [alanine aminotransferase (ALT) and aspartate aminotransferase (AST)] and bilirubin levels prior to starting treatment with ZYTIGA®, every two weeks for the first three months of treatment, and monthly thereafter. Promptly measure serum total bilirubin, AST, and ALT if clinical symptoms or signs suggestive of hepatotoxicity develop. Elevations of AST, ALT, or bilirubin from the patient’s baseline should prompt more frequent monitoring. If at any time AST or ALT rise above five times the upper limit of normal (ULN) or the bilirubin rises above three times the ULN, interrupt ZYTIGA® treatment and closely monitor liver function. Increased ZYTIGA® Exposures with Food ZYTIGA® must be taken on an empty stomach. No food should be eaten for at least two hours before the dose of ZYTIGA® is taken and for at least one hour after the dose of ZYTIGA® is taken. Abiraterone Cmax and AUC0-∞ (exposure) were increased up to 17- and 10- fold higher, respectively, when a single dose of abiraterone acetate was administered with a meal compared to a fasted state. Adverse Reactions The most common adverse reactions (≥10%) are fatigue, joint swelling or discomfort, edema, hot flush, diarrhea, vomiting, cough, hypertension, dyspnea, urinary tract infection and contusion. The most common laboratory abnormalities (>20%) are anemia, elevated alkaline phosphatase, hypertriglyceridemia, lymphopenia, hypercholesterolemia, hyperglycemia, elevated AST, hypophosphatemia, elevated ALT and hypokalemia. Drug Interactions Based on in vitro data, ZYTIGA® is a substrate of CYP3A4. In a drug interaction trial, co-administration of rifampin, a strong CYP3A4 inducer, decreased exposure of abiraterone by 55%. Avoid concomitant strong CYP3A4 inducers during ZYTIGA® treatment. If a strong CYP3A4 inducer must be co-administered, increase the ZYTIGA® dosing frequency only during the co-administration period [see Dosage and Administration (2.3)]. In a dedicated drug interaction trial, co-administration of ketoconazole, a strong inhibitor of CYP3A4, had no clinically meaningful effect on the pharmacokinetics of abiraterone. ZYTIGA® is an inhibitor of the hepatic drug-metabolizing enzyme CYP2D6. Avoid co-administration with CYP2D6 substrates with a narrow therapeutic index. If alternative treatments cannot be used, exercise caution and consider a dose reduction of the CYP2D6 substrate drug. In vitro, ZYTIGA® inhibits CYP2C8. There are no clinical data on the use of ZYTIGA® with drugs that are substrates of CYP2C8. Patients should be monitored closely for signs of toxicity related to the CYP2C8 substrate if used concomitantly with abiraterone acetate. Use in Specific Populations Do not use ZYTIGA® in patients with baseline severe hepatic impairment (Child-Pugh Class C). Please see Brief Summary of Prescribing Information on adjacent pages. © Janssen Biotech, Inc. 2013

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Please see Important Safety Information on back, and Brief Summary of Prescribing Information on adjacent pages. Patient insurance benefit investigation is provided as a service by The Lash Group, Inc., under contract for Janssen Biotech, Inc. In this regard, The Lash Group, Inc., assists healthcare professionals in the determination of whether treatment could be covered by the applicable third-party payer based on coverage guidelines provided by the payer and patient information provided by the healthcare provider under appropriate authorization following the provider’s exclusive determination of medical necessity. Importantly, insurance verification is the ultimate responsibility of the provider. Third-party reimbursement is affected by many factors. Therefore, The Lash Group, Inc., and Janssen Biotech make no representation or guarantee that full or partial insurance reimbursement or any other payment will be available. This information is provided as an information service only. While The Lash Group, Inc., tries to provide correct information, it and Janssen Biotech make no representations or warranties, express or implied, as to the accuracy of the information. In no event shall The Lash Group, Inc., or Janssen Biotech or its employees or agents be liable for any damages resulting from or relating to the services. All providers and other users of this information agree that they accept responsibility for the use of this service. Janssen Biotech assumes no responsibility for, and does not guarantee the quality, scope, or availability of the services including but not limited to reimbursement support services, patient education, and other support services. Each provider, not Janssen Biotech, is responsible for the services they provide. These support services have no independent value to providers apart from the product and are included within the cost of the product. © Janssen Biotech, Inc. 2013

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